Project Summary/Abstract In the United States, nearly a tenth of the population has type 2 diabetes mellitus (T2DM). The chronic hyperglycemia found in this disease causes angiopathy, leading to kidney failure, blindness, amputation, stroke, and heart attack. Some of the medicines used to treat T2DM have an adverse side effect profile, underscoring the need to develop new anti-hyperglycemic agents. The recently discovered Palmitic Acid esters of HydroxyStearic Acids (PAHSAs) have been shown to improve blood glucose levels by increasing insulin release and insulin sensitivity through their activity on free fatty acid receptors-1 and -4. However, the effect that the chemical structure has on biological activity and the origins of PAHSAs remain unknown. The Specific Aims of this proposal are to: 1) develop a synthetic platform for PAHSAs and determine the relationship between PAHSA structure and anti-diabetic activity and 2) determine the biosynthetic origins of PAHSAs. Uncovering the structural elements responsible for the anti-diabetic activity of PAHSAs may provide a lead structure for a novel treatment in the fight against diabetes. Furthermore, elucidation of the biosynthesis of PAHSAs may spur future studies that would allow for treatment of this disease by helping patients with diabetes increase their own endogenous PAHSA synthesis.